Melanoma is a type of skin cancer whose incidence has steadily risen particularly in the Caucasian population over the last few decades. In the advanced stages of the disease, melanomas are characterized with a high metastatic potential, are extremely refractory to adjuvant therapies like radio- or chemotherapy and are often fatal. These observations underscore the need for developing novel markers indicative of metastatic potential and improved treatment modalities targeting the metastatic component of the disease. Melanoma differentiation associated gene-9 (mda-9), also known as syntenin, is an adapter molecule that plays important roles in diverse cell signaling mechanisms. Recent experiments document an association of mda-9/syntenin with metastatic cancers. A gradual increase in mda-9/syntenin expression level was observed with the progression of melanomas and overexpression of mda-9/syntenin in poorly metastatic breast or gastric cancer cells increased their invasion and migration properties. Inhibition of mda-9/syntenin by siRNA suppressed the invasive phenotype of aggressive melanoma cells indicating that mda-9/syntenin might play a key role in mediating the metastatic process. Based on these findings, the studies in this proposal will determine the significance of mda-9/syntenin in melanoma progression through the following specific aims: i) To correlate changes in mda-9/syntenin expression with different stages of human melanoma, ii) To analyze the effect of overexpresssion of mda-9/syntenin on poorly metastatic melanomas and iii) To target mda-9/syntenin as a potential therapeutic intervention for metastatic melanomas. Successful completion of these studies will facilitate the understanding of mda-9/syntenin in melanoma metastasis and its development as a diagnostic and/or prognostic tool and a therapeutic target for metastatic melanomas.Dr. Sarkar qualifies as Category #1 in the Guidelines as a New Investigator with extensive expertise in melanoma biology. This P&F study will utilize the services of Cores A, B, C, and D.